Mol Neurobiol DOI 10.1007/s12035-016-0313-5

Endocannabinoid System: the Direct and Indirect Involvement in the Memory and Learning Processes—a Short Review

Marta Kruk-Slomka1 & Agnieszka Dzik1 & Barbara Budzynska1 & Grazyna Biala1

Received: 30 September 2016 /Accepted: 21 November 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com

Abstract The via Ca 2+ Calcium ions (CB: CB1 and CB2) receptors and their endogenous ligands CB Cannabinoid is directly and indirectly involved in many physiological func- CB1KOS CB1 genetic knockout mice tions, especially in memory and learning processes. Extensive CB2KOS CB2 receptor genetic knockout mice studies reported that this system strictly modulates cognition- CFC Contextual fear conditioning related processes evaluated in various animal models. CNS Central nervous system However, the effects of on the cognition have ECS Endocannabinoid system been contradictory. The cannabinoid compounds were able to ETM Elevated T-maze both impair or improve different phases of memory processes FAAH Fattyacidamidhydrolase through direct (receptor related) or indirect (non-receptor GABA Gamma-aminobutyric acid related) mechanism. The memory-related effects induced by IA Inhibitory avoidance the cannabinoids can be depended on the kind of cannabinoid Intra-BLA Intra-basolateral amygdala compound used, dosage, and route of administration as well as Intra-PLC Intra-prelimbic on the memory task chosen. Therefore, the objectives of this i.p. Intra-peritoneally paper are to review and summarize the results describing the MAGL role of endocannabinoid system in cognition, including NADA N-arachidonoyl dopamine various stages of memory. NAGly N-arachidonylglycine OEA Oleoylethanolamine Keywords Endocannabinoid system . Cannabinoid OF Open field receptors . Memory and learning . Cognition . Animal models ORT Object recognition task of memory PA Passive avoidance PCR Polymerase chain reaction PEA RAM Radial arm maze Abbreviations VTA Ventral tegmental area 2-AG 2-Arachidonoylglycerol WMT Water maze test Δ-9-THC Δ-9-Tetrahydrokannabinol AEA Pharmacology of the Endocannabinoid System

* Marta Kruk-Slomka The endocannabinoid system (ECS) is a lipid signaling [email protected] system, which is functionally active since the early stages of brain development and remains active during both prenatal 1 Department of Pharmacology and Pharmacodynamics, Medical and post-natal life [1–3]. This system consists of the cannabi- University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland noid (CB) receptors, their endogenous ligands, the enzymes Mol Neurobiol for the synthesis and degradation of endocannabinoids, and schizophrenia [20, 21], depression [22], and bipolar disorders the reuptake transport system [4]. [23]. Moreover, in CB2-knockout mice, schizophrenia-like The discovery of specific CB receptors, followed by iden- symptoms were observed [24]. Additionally, the CB2 receptors tification of their endogenous ligands, gave an opportunity to modulate both excitatory [25, 26] and inhibitory synaptic trans- the extensive research on the significance of this system for missions in the hippocampus [27–29]. It has been reported that the proper functioning of the organism. CB receptors were the activation of CB2 receptors reduces pain [30], impulsive discovered in late 1980s and then were divided into two dif- behavior [31], locomotor activity of rodents [22, 32, 33], and ferent subtypes of G protein-coupled receptors [5]. Currently, vomiting of ferrets [34]. Stimulation of CB2 receptors also two types of CB receptors are known. The pharmacological decreases the excitability of peripheral sensory neurons [30], effects are mainly exerted through the activation of Gi/o cortical pyramidal neurons [35], and dopaminergic neurons in protein-coupled membrane receptors CB1 and CB2. Despite the ventral tegmental area (VTA) [36](Fig.1). the fact that both CB1 and CB2 receptors belong to the group As mentioned earlier, endocannabinoids are synthesized on of G protein-coupled receptors and are characterized by sig- demand from lipid precursors derived from the enzymatic nificant homology, they differ in their function and specificity cleavage of cell membrane constituents in response to neuronal of cellular expression [6]. membrane depolarization or immune cell activation and are CB1 receptors are located mainly in the central nervous released from post-synaptic membranes as retrograde messen- system (CNS), and they are one of the most abundantly gers onto presynaptic terminals of excitatory or inhibitory char- expressed neuronal receptors in the CNS, which suggests their acter, thus suppressing both inhibitory and excitatory signaling important role in the function of the CNS. These receptors are within specific neuronal area. Endocannabinoids control syn- widely expressed in multiple brain areas with the highest con- aptic plasticity by an influence on neurotransmitter release [5, centration in the regions associated with cognition and move- 6, 18]. They have affinity for both CB1 and CB2 receptors [6]. ment like amygdala, hippocampus, septum, brain cortex, Henceforth, two endogenous cannabinoids (endocannabinoids) globus pallidus, substantia nigra, cerebellum, and lateral cau- were discovered: arachidonoylethanolamide (anandamide date putamen [4]. Additionally, they are also present at lower (AEA)) and 2-arachidonoylglycerol (2-AG) [5]. They remain concentration in a variety of peripheral tissues, both on sen- the two most studied endogenous substances from the others sory nerve fibers and in the autonomic nervous system [6–8]. known so far, including , noladin ether, CB1 receptors are localized presynaptically on glutamatergic palmitoylethanolamide (PEA), N-arachidonoyl dopamine and gamma-aminobutyric (GABA) acid axon terminals [9]. In (NADA), N-arachidonylglycine (NAGly), , and the hippocampus, CB1 receptors are located mainly in oleoylethanolamine (OEA) [37](Table1). GABA-ergic, inhibitory interneurons. They are also present 2-AG is mainly produced in the CNS, and AEA is produced in the hippocampal glutamatergic axon terminals, but their at low levels in the periphery and the CNS [38]. Production of concentration is at least 20 times lower than in the presynaptic endogenous cannabinoids is increased in response to patho- areas of this brain structure. Activation of CB1 receptors is genic stimulus. Particularly important to immune modulation connected with inhibition of adenyl cyclase as well as calcium is a fact that the production of endocannabinoids is stimulated channels and leads to activation of potassium channels; thus, it by activation of immune cells (macrophages) and dendritic contributes to short-term depression of neurotransmitter re- cells, and stimulated immune cells have reduced the expres- lease in corticostriatal GABA-ergic and glutamatergic neurons sion of endocannabinoid-degrading enzymes [39]. [5]. CB1 receptors are also present on noradrenergic termi- Endocannabinoids are metabolized by degradative enzymes nals, and their blockade increases release of norepinephrine like fatty acid amid hydrolase (FAAH), which metabolizes in limbic regions [10, 11]. Owing to their localization, CB1 AEA as well as 2-AG, and monoacylglycerol lipase receptors control both cognitive process and emotional behav- (MAGL), which metabolizes 2-AG [8]. ior, including stress, fear, or anxiety [12–17]bymodulating It should be also noted that there are two novel G protein- neuronal signaling and synaptic plasticity [18]. coupled orphan receptors GPR55 and GPR119, which have In turn, CB2 receptors are present mainly peripherally and been recently defined as CB receptors [40]. Though showing are the most abundant in the immune system in a variety of virtuallynoapparenthomologytoeitheroftheclassicalCB immune cells including B lymphocytes, natural killer cells, receptors, GPR55 was identified as a novel CB receptor [41]. monocytes, macrophages, polymorphonuclear neutrophils, The CB-sensitive receptor GPR55 was identified and cloned by and T cells [4, 6]. Thus, they are mainly involved in immune Sawzdargo et al. [42]. Its presence in the brain, including the system functions [6, 19]. However, the CB2 receptors have also hippocampus, has been proved by using quantitative polymer- been found in microglial cells in the CNS. The gathered data ase chain reaction (PCR) [43, 44]. GPR55 activity can be mod- suggests that CB2 receptors modulate neuronal function and ulated by phytocannabinoids and endocannabinoids [38, 44]. play a role in psychiatric disorders. Polymorphism of CB2 The endocannabinoids that have affinity for GPR55 receptors receptor gene encoding CB2 receptors in humans is related to probably include AEA, 2-AG, PEA, and others [45]. Moreover, Mol Neurobiol

Fig. 1 The distribution of CB receptors in the CNS and periphery

Table 1 The chemical structure of endocannabinoids Anandamide (5Z,8Z,11Z,14Z)-N-(2- OH

NH hydroxyethyl)icosa-5,8,11,14- O tetraenamide

3CH 2-arachidonoylglycerol 1,3-dihydroxypropan-2-yl OH

OH O (5Z,8Z,11Z,14Z)-icosa- O 5,8,11,14-tetraenoate

3CH Virodhamine 2-aminoethyl 2NH (5Z,8Z,11Z,14Z)-icosa- O O 5,8,11,14-tetraenoate

3CH Noladin ether 2-[(5Z,8Z,11Z,14Z)-icosa- OH O OH 5,8,11,14-tetraenoxy]propane- 1,3-diol

3CH Mol Neurobiol

Table 1 (continued) Palmitoylethanolamide N-(2- OH hydroxyethyl)hexadecanamide NH

O

3CH N-Arachidonoyl (5Z,8Z,11Z,14Z)-N-[2-(3,4- H O

dopamine dihydroxyphenyl)-ethyl]icosa- N N CH3 5,8,11,14-tetraenamide O

O

N-Arachidonylglycine (5Z,8Z,11Z,14Z)-N-Icosa- 3CH 5,8,11,14-tetraenoylamino- OH

acetic acid O NH

O oleamide (Z)-octadec-9-enamide NH2 O

3CH Oleoylethanolamine (Z)-N-(2- hydroxyethyl)octadec-9-

enamide 3CH

O NH OH

recent studies suggest that L-α-, which Langerhans. OEA is one of the most potent ligands for these activates GPR55 but not CB1 or CB2 receptors, could also be receptors, but they are not activated by AEA and only weakly its endogenous [46, 47]. Contrariwise, by PEA [41]. However, the pharmacology of both GPR55 and (CBD), a major constituent of sativa,isaGPR55 GPR119 is enigmatic, and its adaptive role in the brain remains antagonist, with low affinity for CB1 receptors [44, 48]. In turn, unknown. Therefore, the explanation of their exact role in the GPR119 receptors are expressed on enteroendocrine L cells of ECS requires further studies. the gastrointestinal tract. They regulate the release of the anti- As we described previously, the ECS, through CB recep- diabetic peptide glucagon-like peptide-1 [49–51]. These recep- tors, and its interactions with a multitude of neurotransmitters tors are also found on pancreatic β cells in the islets of and receptors are directly and indirectly involved in many Mol Neurobiol physiological and physical functions [52–61]. In the recent SR147778 (1.0 mg/kg, i.p.) has in fact prevented the impair- years, a large number of studies focused on learning and mem- ment. These findings demonstrate that an acute administration ory processes. The substances exerting their action through of WIN 55,212-2 dose-dependently impairs the acquisition of ECS are able to both impair and enhance different phases of memory in the CFC test, which is a hippocampus-dependent memory formation through direct and indirect mechanisms. learning and memory task and does not affect tone fear con- However, the results of multiple studies show that manipula- ditioning, which is considered independent of the hippocam- tions performed on the ECS in reference to learning and mem- pus [73, 74]. Likewise, chronic administration of WIN ory bring contradictory results. Thus, the purpose of this paper 55,212-2 significantly impaired spatial memory in rats evalu- is to review and summarize findings connected with the in- ated in the WMT [75]. Additionally, Kruk-Slomka et al. [64] volvement of the ECS in the different memory stages. revealed that WIN 55,212-2 impaired both acquisition and consolidation of memory in PA test in mice. The evidence gathered from this experiment reaffirms that the effects of The Role of CB Receptor in the Memory-Related the CB receptor agonists are selective for the hippocampus- Responses in Animal Models of Memory: CB dependent aversive memories in rats. Receptor Agents Contradictory data concerning the influence of CB1 on memory consolidation has also been reported. It has been CB1 Receptor Ligands demonstrated that post-training administration of CB1 recep- tor agonist HU-210 as well as a combined CB1/CB2 receptor The influence of the CB1 receptor ligands on memory and agonist WIN 55,212-2 attenuated consolidation of memory in learning processes has been widely documented by various the CFC test, the WMT, and the ORT [7, 76–78]. Indeed, experiments and clinical studies [8, 62–66]. Nevertheless, Maćkowiak et al. [77] investigated the role of CB1 receptors the results are still contradictory. In this part of the present in hippocampal-dependent memory consolidation using HU- elaboration, we will summarize the effects of the CB1 receptor 210. The results indicated that HU-210 impaired the consoli- ligands, including CB1 receptor agonist and CB1 antagonists dation of fear memory in the CFC test. These detrimental (and inverse agonists) on different memory stages. effects were abolished by a CB1 Studies have demonstrated that an acute administration of AM251. These findings may suggest the involvement of synthetic CB1 receptor agonists: CP55940 and HU-210 atten- CB1 receptors in memory and learning processes. The results uated acquisition of memory in various animal models, e.g., of the studies indicated also that AM251 blocked the effects of the water maze test (WMT), the object recognition task HU-210 on freezing behavior but did not affect memory con- (ORT), and the contextual fear conditioning (CFC) test solidation in the CFC on its own. Thus, the blockade of CB1 [67–71]. Similarly, Mazzola et al. [68] and others [71]con- receptors does not affect consolidation of contextual memory firmed these effects of direct activation of natural CB1 recep- [79] and disrupts memory consolidation in a step-down inhib- tor agonist—Δ9-tetrahydrokannabinol (Δ9-THC). Δ9-THC itory avoidance (IA) [80, 81]. (3.0, 5.0, and 6.0 mg/kg) injected intra-peritoneally (i.p.) Similar effects of WIN 55,212-2 on memory consolidation 30 min before the learning trial significantly impaired memory were observed in spatial memory formation using the WMT acquisition using the passive avoidance (PA) task in rats. This [78]. Yim et al. administered WIN 55,212-2 systemically and deterioration was reversed by pretreatment with 1 mg/kg of intra-cranially to assess both methods of drug delivery. They (SR141716A), a CB1 receptor antagonist. demonstrated that this CB1/CB2 receptor ligand impairs the Moreover, indirect stimulation of CB1 receptors impaired ac- consolidation of long-term spatial memory. Similar long-term quisition of memory in the recognition memory test [72]. memory impairments were observed in both systemic injec- In turn, Pamplona and Takahashi investigated whether tions and intra-hippocampal infusions of WIN 55,212-2. As CB1/CB2 receptor agonist, WIN 55,212-2, is able to influence CB2 receptors are not expressed in the hippocampus, there- the acquisition of fear conditioning using tone and contextual fore, the observed impairments provide an indirect support versions [69]. They revealed that this compound (2.5 and that this effect was reached by targeting CB1 receptors [78]. 5.0 mg/kg, i.p.), administered before conditioning and before Nonetheless, it has been noted that intra-basolateral amygdala testing, impaired memory processes in the CFC and did not (intra-BLA infusion) of WIN 55,212-2 facilitated memory affect the freezing behavior induced by tone presentation; consolidation in rats evaluated in the IA task or had no effect therefore, non-state-dependent effects of WIN 55,212-2 on in the mentioned animal model [82, 83]. On the other hand, tested animals were observed. During the course of further post-training intra-hippocampal injection of this drug im- studies, selective CB1 antagonists (SR141716A and paired consolidation of memory in several behavioral tasks SR147778) were administered, in order to establish whether [84]. WIN 55,212-2 was also evaluated in the experiments impaired contextual conditioning would be prevented. conducted by Clarke et al. [76]. They examined the effects Preadministration of SR141716A (1.0 mg/kg, i.p.) or of post-training activation of hippocampal CB receptors on Mol Neurobiol the consolidation of object recognition memory. The results of rimonabant were also shown in the experiments performed the study were in agreement with the evidence provided by by Takahashi et al. [88]. Administration of 1.0 mg/kg of Yim et al. [78]. WIN 55,212-2 impaired the consolidation rimonabant produced an improvement in memory acquisition phase of memory formation. Amnestic effect of this com- and consolidation in the ETM task. Neither lower (0.5 mg/kg) pound was completely reversed by coadministration of CB1 nor higher (2.0 mg/kg) doses were able to improve acquisi- receptor antagonist, AM251, as well as mimicked by CB1 tion. Additionally, facilitation of short-term olfactory memory receptor agonist, ACEA, but not by CB2 receptor agonist, in the social recognition test was described by Terranova et al. JWH-015 [78]. These findings are also in agreement with [88]. On the other hand, Marsicano and colleagues failed to the results published by Moshfegh et al. [85]. They used a prove any effect of rimonabant on the consolidation of aver- step-down PA task as a model of learning. The results indicat- sive memories [94]. This result may be accounted to the dif- ed that post-training administration of WIN 55,212-2 pro- ferent mouse strain. The single dose used by Marsicano et al. duced an amnestic response. All the effects described previ- [94] was also higher than the maximum dose used in the ously endorsed the hypothesis that the memory impairments studies described previously. were due to activation of hippocampal CB1 receptors. AM251 is a member of the same CB group of Systemic administration of CB1 receptor antagonists, e.g., diarylopyrazoles as SR141716A, presenting the features of rimonabant (SR141716A) or AM251, has been tested in var- CB1 receptor antagonist and [4]. The post- ious learning paradigms alone or coadministered with CB1 training administration of AM251 interfered consolidation of agonists [61, 63, 64, 81, 86–89]. memory-related processes in the step-through IA task or CFC SR141716A is a selective and potent CB1 receptor antago- task [82, 87]. De Oliveira Alvares et al. [81] investigated the nist [90]. It also presents features of an inverse agonist [91]. An effects of intra-hippocampal administration of AM251 in two acute, pretraining administration of SR141716A facilitated the behavioral tasks: the IA and the open field (OF) habituation acquisition of memory in rodents observed in the PA test, the task. The results indicated that AM251 exerted a disruptive elevated T-maze (ETM) test, and social recognition memory effect on memory consolidation in the IA test, but not in the task [61, 89] and impaired the acquisition of memory assessed OF habituation test. Similarly, Kruk-Slomka and Biala [63] in the spatial memory test [92]. Additionally, systemic, post- confirmed that an acute injection of AM251 improved the training administration of rimonabant enhanced memory con- short-term and long-term memory stages (acquisition, consol- solidation in the radial arm maze (RAM) [89]. Also, Robinson idation, and/or retrieval) in the IA task. The effect seemed to et al. studied the effects of SR141716A on spatial learning and be purely mnemonic since the drug showed no motor perfor- memory formation using the WMT [92]. Two experiments mance effects, which could favor a false positive for the inter- were performed. In the first one, rimonabant was administered mediate dose in the IA test session. It needs to be highlighted i.p., before or immediately after training. The results indicated that the amnestic effect took place with the lower, more selec- that systemic administration before training induced deficits in tive dose, not with the higher one (that one could bind to the acquisition of spatial reference memory; however, pretraining non-specific targets in the hippocampus). The different re- before drug treatment eliminated this effect. The experiment sponses observed in two behavioral tasks require explanation. revealed that rimonabant-induced memory deficits appeared The findings of the study suggest that hippocampal as a result of anxiogenic effects of the drug. Post-training injec- endocannabinoids are not acting upon the consolidation of tions had no effect. In the second experiment, rimonabant was the OF habituation task. The fact that the OF was not recruited administered intra-hippocampally during the training and the and the IA was sensitive to AM251 raises the possibility that results indicated that this drug enhanced acquisition learning this system requires some degree of aversiveness or alertness and exerted no effect on consolidation of memory. to be recruited. The impairing effect of AM251 on memory Subcutaneous injections did not affect memory in any way [92]. consolidation was also confirmed by Bucherelli et al. in 2006 The results from these described experiments demonstrated [87]. De Oliveira Alvares and colleagues replicated the previ- that rimonabant produced various effects dependent upon the ous findings [80]. Afterwards, Bialuk and Winnicka [4]per- route of administration, the timing of infusion, and the dose of formed a study in an attempt to determine the influence of the drug. Similarly, Lichtman reported an improvement of different doses of AM251 on recognition memory. In order memory acquisition induced by administration of to evaluate the effects of AM251 on acquisition of informa- SR141716A [93]. Likewise, Wolff and Leander showed the tion, the drug was given 15 min before learning trial, and to enhancement of the consolidation processes when the animals establish its influence on consolidation of information, it was were tested in the RAM test [89]. Furthermore, Wolff and injected immediately after the trial in the ORT. The results of Leander [89] proved a dose of 1.0 mg/kg of SR141716A to the study indicated that AM251 significantly improved both be effective. The higher dose of 3.0 mg/kg did not improve the acquisition and consolidation of information; however, these consolidation, what is consistent with the results obtained by effects were observed only when dose of 1 mg/kg was admin- Lichtman [93] in the same task. Pro-cognitive effects of istered. Higher doses did not exert any influence on it. The Mol Neurobiol memory-improving effect is in an agreement with the results different way. Such contradictory findings may be connected obtained in experiments with SR141716A [4]. with differences in behavioral tasks used, handling proce- Interesting experiments in the context of our paper seem to dures, e.g., time of drug administration, the kind of drug treat- be the studies of Tan et al. [95]. The authors used CB antag- ment, or other experimental conditions, as well as doses and onist, agonist, and reuptake inhibitor, AM251, WIN 55,212-2, CB compounds selected. Therefore, future studies may help to and AM404, respectively. The substances were administered discover and describe the precise role and character of differ- bilaterally as an intra-BLA and intra-prelimbic (intra-PLC) ent CB1 receptor compounds (Table 2). microinfusion in rats. The results indicated that pharmacolog- ical inhibition of intra-BLA CB1 receptor transmission dose- dependently blocked the acquisition of olfactory fear memory, The Role of CB Receptor in the Memory-Related simultaneously leaving unaffected recall and consolidation of Responses in Animal Models of Memory: CB2 these memories in an olfactory fear conditioning procedure. In Receptor Agents addition, activation of CB1 receptor transmission or inhibition of the endocannabinoid reuptake within BLA strongly poten- The specific impact of CB2 receptor ligands on the cognition- tiated the acquisition of fear memory. Moreover, fear memory related processes seems to be more complex and still not pre- formation, mediated by CB1 receptor, was blocked when the cisely explored. In this part of the present elaboration, we can medial prefrontal cortex (mPFC) was pharmacologically discuss only few results concerning the effects of the CB2 inactivated before intra-BLA activation of CB1. These find- receptor ligands on memory and learning. ings are consistent with the report presented by Campolongo The results of the studies suggest that the activation of CB2 et al., which showed that intra-BLA activation of CB1 recep- receptors evokes diverse effects depending on the brain area. tors can potentiate the encoding of associative memory for IA Chronic stimulation of CB2 receptors in the hippocampus learning [82]. Previous studies conducted by Roche et al. [96] increases excitatory synaptic transmission [26], and simulta- indicated that intra-BLA blockade of CB1 receptor transmis- neously, deletion of CB2 in the same brain structure leads to sion with rimonabant inhibits the formation of context- reduction in dendritic spine density [25]. Chronic activation of dependent fear memory. Overall, the previously mentioned CB2 also increases GABA-A receptor expression [28], yet it findings suggest that CB1 receptor-dependent transmission does not affect the inhibitory synaptic transmission in the hip- within the BLA can influence the magnitude of emotional pocampus. CB2 receptor agonists reduce membrane excitabil- memory encoding. Additionally, the memory-improving ef- ity of cortical neurons [35] leaving hippocampal neurons un- fects of AM251 observed in this study were in agreement with affected [26]. CB2 receptor agonists also increase chloride the results obtained by Riedel and Davies [97]. They have conductance [35]. reported that while the CB1 receptor agonists impair memory JWH133 is a selective CB2 receptor agonist. Kruk-Slomka formation, the CB1 receptor antagonists reverse these deficits et al. [64] established that the lower dose of JWH133 or act as memory enhancers. (0.5 mg/kg) exerted no influence on the acquisition but en- Lin et al. studied the effects of another CB1 receptor antag- hanced the consolidation of long-term memory in the PA test. onist AM281 on the formation of contextual fear memory in JWH133 (at higher doses of 1.0 and 2.0 mg/kg) improved the adult mice [98]. AM281 (2.5 mg/kg) was injected both intra- acquisition or consolidation of long-term memory. An acute peritoneally and intra-hippocampally to assess the influence on pretraining and post-training administration improved memory acquisition. These results indicate that CB1 receptor- memory-related responses evaluated in the PA test. mediated signaling within the area of hippocampus negatively The CB2 antagonist AM630 is one of the most studied regulates the acquisition in contextual fear memory task. Thus, exogenous CB receptor ligands. It acts as an inverse agonist AM281 seems to be a good candidate for memory enhance- both at CB2 and CB1 receptor sites [100]. Kruk-Slomka et al. ment; however, further studies in animal models of cognitive [64] revealed that AM630 significantly improved memory. dysfunctions are still required. In the context of this subject, it The higher doses of AM630 (2.0 and 3.0 mg/kg) induced should be noted that Wise et al. decided to determine the effects statistically significant increase in antioxidant properties of of a relatively novel and potent CB1 receptor antagonist CE on brain tissue and evoked long-term memory improvement in memory processes. CE is structurally distinct from rimonabant. behavioral test. However, the lower dose (0.5 mg/kg) was Wise and colleagues observed that CE significantly enhanced found inactive; it does not alter memory-related responses in memory consolidation in the RAM procedure [99]. the PA test in mice. As we described previously, the influence of the CB1 re- It has been revealed in behavioral studies described previ- ceptor ligands on memory and learning processes has been ously that both a selective CB2 receptor agonist JWH133 and widely documented by various experiments and clinical stud- a competitive CB2 receptor antagonist AM630 significantly ies. Although CB1 receptor ligands are able to improve as improved long-term memory acquisition and consolidation in well as to impair memory, each of them affects memory in a the PA test [64]. In contrast to these findings, García-Gutiérrez Mol Neurobiol

Table 2 The chemical structure of CB1 receptor ligands CB1 receptor agonists CP-55940 2-[(1R,2R,5R)-5-hydroxy-2- OH (3- OH hydroxypropyl)cyclohexyl]- 5-(2-methyloctan-2-yl)phenol CH3 OH 3CH

CH3 HU-210 (6aR,10aR)-9- OH

(hydroxymethyl)-6,6- OH dimethyl-3-(2-methyloctan-2- CH3 3CH yl)-6a,7,10,10a- O CH3 3CH CH tetrahydrobenzo[c]chromen- 3 1-ol Delta(9)- (6aR,10aR)-6,6-dimethyl-9- CH2 methylidene-3-pentyl- OH e 7,8,10,10a-tetrahydro-6aH- 3CH O CH CH 3 benzo[c]chromen-1-ol 3

Cl Arachidonyl-2'- (5E,8E,11E,14E)-N-(2-

NH

chloroethylamide chloroethyl)icosa-5,8,11,14- O tetraenamide

3CH CB1 receptor antagonists

CH CE 1-[7-(2-Chlorophenyl)-8-(4- 3 N N O chlorophenyl)-2- Cl N N

N NH2 methylpyrazolo[1,5-a]-[1,3,5] O NH O S Cl OH triazin-4-yl]-3- CH3 ethylaminoazetidine-3- carboxylic acid amide benzenesulfonate Mol Neurobiol

Table 2 (continued) Rimonabant, 5-(4-chlorophenyl)-1-(2,4- N O SR141716A dichlorophenyl)-4-methyl-N- NH N N piperidin-1-ylpyrazole-3- 3CH

Cl carboxamide Cl

Cl Surinabant, 5-(4-bromophenyl)-1-(2,4- N O SR 147778 dichlorophenyl)-4-ethyl-N- NH N piperidin-1-ylpyrazole-3- N

3CH carboxamide Cl Cl

Br AM251 1-(2,4-dichlorophenyl)-5-(4- N O NH iodophenyl)-4-methyl-N- N N piperidin-1-ylpyrazole-3- 3CH Cl Cl carboxamide

I AM281 1-(2,4-dichlorophenyl)-5-(4- O N O iodophenyl)-4-methyl-N- NH morpholin-4-ylpyrazole-3- N 3CH N

carboxamide Cl Cl

I CB1/CB2 receptors agonists WIN-55212-2 (11R)-2-methyl-11- O [(morpholin-4-yl)methyl]-3- N O

(naphthalene-1-carbonyl)-9- N CH3 oxa-1-

azatricyclo[6.3.1.0⁴,¹²]dodeca O -2,4(12),5,7-tetraene

et al. [25] have shown that JWH133 enhanced memory con- The enhancement of memory caused by both CB2 antago- solidation, but AM630 impaired memory-related responses in nist and CB2 agonist obtained by Kruk-Slomka et al. [64]may the step-down IA test. be connected with pharmacokinetic properties of used CB2 Mol Neurobiol receptor ligands, i.e., JWH133 and AM630. It needs to be in these processes [105]. The results achieved by Litvin et al. underlined that a CB2-selective agent AM630 acts as an in- [9] of increased cognitive abilities in the CB1KOS mice are verse agonist rather than as a Bsilent^ antagonist. The inverse consistent with the previous reports describing enhanced cog- efficacy at CB2 receptors and the CB2/CB1 affinity ratio has nitive performance in several other tests like active avoidance been indicated for AM630 (CB2/CB1 affinity = 165); there- memory [106], CFC [107], and ORT [108, 109]. It has been fore, AM630 has been found to act as a low-affinity partial also reported that CB1-deficient mice display normal acquisi- agonist in some experiments but as a low-potency inverse tion and impaired extinction of both spatial reference memory agonist in another study [101]. The pharmacological proper- [110, 111] and cued fear memory [59]. CB1KOS mice also ties of AM630 are more complex. It has been revealed that present reduced working memory [58]. Although the param- AM630 acts as an inverse agonist at CB2 receptors as well as eters of PA concerning the memory-related effects stayed un- an inverse agonist at CB1 receptors [102]; therefore, it may be affected [36], the contextual fear memory was reported both to proposed that both agonist and antagonist of CB2 receptors be enhanced and to be impaired [56]. used in this study may improve memory and learning process- Similarly, for a complete understanding of the mechanism es through CB1 as well as CB2 receptors. Further experiments underlying the action of CB2 receptors, it will be necessary to are required to explain this phenomenon. determine the role of CB2 receptors in regulating various To sum up, it should be mentioned that the specific impact properties of synaptic transmission. It also needs to be evalu- of CB2 receptor ligands on the cognition-related processes ated whether the affected immune functions in CB2 receptor seems to be more complex and still not precisely evaluated. genetic knockout mice (CB2KOS) influence the processes Similarly as CB1 receptor ligands, CB2 receptor ligands are involved in learning and memory. Li and Kim [112]utilized able to attenuate as well as facilitate memory and learning both CB2-deficient mice and acute blockade of CB2 receptors processes. These different memory effects may be associated by AM630. The results indicated that the inhibition of CB2 by mainly with pharmacokinetic properties of tested CB2 recep- a specific CB2 receptor antagonist AM630 had no effect on tor ligands as well as with antioxidant properties, exhibited by memory acquisition in contrast to the knockout of CB2 recep- both agonists and antagonist of these receptors (Table 3). tors. The findings indicated that acquisition of spatial working memory evaluated in Y-maze in CB2KOS was enhanced in comparison to mice examined in the WMT. The results also The Role of CB Receptor in the Memory-Related indicated that CB2 receptors play diverse roles in regulating Responses in Animal Models of Memory: CB memory. Thus, taken together, the results imply that the ef- Receptor Deficiency fects of CB2 receptor blockade (either through genetic defi- ciency or pharmacological inhibition) are variable. Acute In order to establish the role of CB receptors more accurate blockade with AM630 exerts no effect on memory acquisi- and disentangle the role of endocannabinoid system in mem- tion, implying that downregulation of CB2 receptors needs to ory formation, two strands of research have been implement- be prolonged to induce such effects [112]. ed: knockout mice deficient for CB receptor as well as afore- These all findings indicate that normal acquisition of cued mentioned administration of selective CB receptor antagonist. fear memory is common for both CB1- and CB2-deficient Litvin et al. used a genetic knockout of CB1 receptors mice, but alterations in the working memory are opposite. (CB1KOS) in order to evaluate the role of these receptors in Overall, conclusion leads to the statement that CB1 and CB2 memory formation processes [9]. The CB1KOS and the ani- receptors play a role in modulation of memory processes. mals that received the CB1 antagonist AM251 showed en- Once the role of each type of receptor is fully characterized, hanced levels of social memory relative to their respective either CB1 or CB2 receptor can be selectively targeted for controls in a social discrimination test. These results empha- pharmacological therapeutics to induce the desired results size the role of CB1 receptors in memory formation. The and avoid the unwanted ones. endocannabinoids bind to CB1 receptors in various brain re- gions to modulate behavioral functions in relation to cogni- tion, emotionality, and stress [12, 103]. These results delineate The Role of Endocannabinoids the effects of CB1 receptor inactivation by utilizing conver- in the Memory-Related Responses in Animal Models gent genetic and pharmacological approaches. These paths of of Memory experiments produce similar behavioral profiles resulting in enhancing memory acquisition in the social discrimination As we mentioned previously, AEA and 2-AG are two main test with some differences, which can attest to discrepancies endocannabinoids in the CNS. Lin et al. [2011] examined the between these manipulations. These results extend the role of impact of AM404, an AEA reuptake inhibitor, on the acqui- the ECS in mood and memory [104] and simultaneously are in sition of memory in mice using the CFC paradigm [98]. line with the reports describing a specific role of CB1 receptor AM404 was administered into the dorsal hippocampus Mol Neurobiol

Table 3 The chemical structure of CB2 receptor ligands CB2 receptor agonists JWH 015 (2-methyl-1-propylindol-3- CH3

yl)-naphthalen-1-ylmethanone 3CH N

O

JWH133 [5-(4-methoxyphenyl)-1- CH3 pentylpyrrol-3-yl]- naphthalen-1-ylmethanone N CH3 O O

CB2 receptor antagonists Iodopravadoline, [6-iodo-2-methyl-1-(2- O AM630 morpholin-4-ylethyl)indol-3- N

yl]-(4- I N CH methoxyphenyl)methanone 3

CH3 O O

15 min prior to the conditioning session. The outcome of the URB597 (0.1–1.0 mg/kg), injected 40 min before the learning experiment indicated significant suppression of the fear mem- trial, had a significant enhancing effect on memory acquisi- ory. Moreover, Lin et al. [98] confirmed that the inhibitory tion. Further testing demonstrated that the memory-enhancing effect of AM404 on fear memory formation was mediated effects were inhibited after the pretreatment with 1.0 mg/kg by the activation of CB1 receptor. Taken together, they con- rimonabant. These results are consistent with the previous cluded that AEA-mediated activation of CB1 receptor contrib- studies suggesting that FAAH inhibition enhances place mem- utes negatively to the acquisition of contextual fear memory. ory acquisition in the WMT procedure [113]. The effects of The level of AEA may be also increased by the usage of URB597 on acquisition were also studied [114]. In this exper- FAAH inhibitor. FAAH inhibitor, URB597, increases AEA iment, the authors evaluated the effects and interaction be- levels at those neuronal sites and regions of the brain, where tween URB597 and WIN 55,212-2 using the PA test [114]. AEA is synthesized and released, producing a neuron-specific Learning and memory impairment was elicited by WIN activation of CB1 receptor in those areas. On the contrary, 55,212-2 (1.0 mg/kg) administered 30 min before the acqui- systemic administration of CB1 receptor agonist such as sition trial in rats. URB597 (0.1, 0.3, 1.0 mg/kg) or Δ9-THC produces global activation of all CB1 receptors in SR141716A (1.0 mg/kg) was injected 10 min before WIN the whole brain [68]. 55,212-2 or URB597, respectively. The results indicated that Mazzola et al. [68] accomplished the inhibition of FAAH URB597 at the dose of 0.3 and 1 mg/kg enhanced memory by administering URB597 [68]. The effects of URB597 were acquisition in the PA test. The dose of 0.1 mg/kg exerted no studied both alone and after pretreatment with rimonabant in effects. The cognitive-enhancing effects were blocked by the PA paradigm. The findings of this study revealed that SR141716A. This study also revealed that SR141716A Mol Neurobiol injected separately had no effects on cognition. In conclusion, indicated that post-training infusion of anandamide facilitated these findings suggest that URB597 has potential to protect memory consolidation. It is worth noting that only the small against memory deficits produced by CBs. The results of this dose of AEA infused into the dorsal hippocampus of the male study are in accordance with the other studies in which stim- Wistar rats exerted enhancing effect on memory. Any ulation of the endogenous CB signaling with URB597 en- memory-enhancing effect was observed after the administra- hances acquisition in the PA learning and aversively rein- tion of higher doses. The lack of its efficacy at higher doses forced spatial memory tasks [68, 86, 113]. may be explained by its binding to different areas. At the low As CB1 agonists exert amnestic effects and URB597 in- dose, AEA may mainly target the CB1 receptors. creases endogenous level of CB1 agonist AEA, findings that It should also be noted that the effects of FAAH inhibitor, URB597 enhances memory and this improvement can be OL-135, and of genetic deletion of FAAH in mice were stud- inhibited by CB1 receptor antagonist are puzzling. It is possible ied [115]. Both of these manipulations enhanced the acquisi- that learning improvement produced by FAAH inhibitor is not tion of spatial learning in the WMT. This enhancement was actually mediated by CB1 receptor but is blocked by inhibited by pretreatment with rimonabant, suggesting the role SR141716A due to its inverse agonist effects on CB1 receptor. of CB1 receptors in the observed effects [113, 115, 116]. De Oliveira et al. investigated the role of AEA upon the The research concerning FAAH inhibition opens a new different phases of memory processing [37]. The results were approach for developing medications that act indirectly by evaluated in the step-down IA task. The findings of the study enhancing the actions of endogenous lipid amide mediators,

Table 4 The chemical structure of reuptake inhibitors of endocannabinoids Re-uptake inhibitors AM404 (5Z,8Z,11Z,14Z)-N-(4- OH

O hydroxyphenyl)icosa- NH 5,8,11,14-tetraenamide

CH3

O URB597 [3-(3- NH carbamoylphenyl)phenyl] N- O cyclohexylcarbamate

NH2 O JZL184 (4-nitrophenyl) 4-[bis(1,3- O O benzodioxol-5-yl)- N O hydroxymethyl]piperidine-1- + O N O - OH carboxylate O

OO

OL-135 7-phenyl-1-(5-pyridin-2-yl- N O O

1,3-oxazol-2-yl)heptan-1-one N Mol Neurobiol where they are synthesized and released. It is worth mention- 3. Harkany T, Guzmán M, Galve-Roperh I, Berghuis P, Devi LA, ing that FAAH inhibition might be related to a wide spectrum Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci of therapeutic actions and could also share some of the adverse 28(2):83–92 ; therefore, it is prominent that URB597 4. Bialuk I, Winnicka MM (2011) AM251, cannabinoids receptor possesses potentially beneficial properties and displays no in- ligand, improves recognition memory in rats. Pharmacol Rep – dication of liability for abuse or dependence. Therefore, it has 63(3):670 679 5. Goodman J, Packard MG (2015) The influence of cannabinoids been suggested to improve therapeutic interventions in mem- on learning and memory processes of the dorsal striatum. ory deficit cases (Table 4). Neurobiol Learn Mem 125:1–14 6. Koppel J, Davies P (2008) Targetting the endocannabinoid system in Alzheimer’s disease. J Alz Dis 15(3):495–504 7. Busquets-Garcia A, Puighermanal E, Pastor A, De la Torre R, Conclusion Maldonado R, Ozaita A (2011) Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like re- The results of the studies described in this elaboration sum- sponses. Biol Psychiatry 70(5):479–486 marize the impact of CBs on different stages of memory for- 8. Morena M, Campolongo P (2014) The endocannabinoid system: mation. Many preclinical studies have evaluated the multidi- an emotional buffer in the modulation of memory function. Neurobiol Learn Mem 112:30–43 rectional effects of compounds that directly affect the func- 9. Litvin Y, Phan A, Hill MN, Pfaff DW, McEwen BS (2013) CB1 tioning of the ECS (CB receptor ligands), as well as com- receptor signaling regulates social anxiety and memory. Genes pounds that modulate this function indirectly (inhibitors that Brain Behav 12(5):479–489 degrade endocannabinoids in the brain). 10. Srivastava RK, Lutz B (2012) Dysregulation of hypothalamic- pituitary-adrenal axis in mice lacking CB1 receptor in adrenergic The modulation of the influence of the CB receptor ligands and noradrenergic neurons. 22nd Annual Symposium of the on the different memory stages was widely evaluated in the International Cannabinoid Research Society. Freiburg, Germany behavioral studies. Although both CB1 and CB2 receptor li- 11. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, gands are able to improve as well as to impair memory, each of Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmis- them affects memory in a different way and this subject is still sion in the medial prefrontal cortex: implications for therapeutic unexplored. Thus, further studies, not only behavioral exper- actions. Br J Pharmacol 138:544–553 iments, but also molecular (e.g., the assessment of the density 12. Hill MN, Patel S, Campolongo P, Tasker JG, Wotjak CT, Bains JS of the CB receptors in different brain areas: hippocampus, (2010b) Functional interactions between stress and the prefrontal cortex) and biochemical (e.g., the influence of CB endocannabinoid system: from synaptic signaling to behavioral output. J Neurosci 30:14980–14986 receptor ligands on the neurotransmitter and metalloprotein- 13. Lafenetre P, Chaouloff F, Marsicano G (2007) The endocannabinoid ase levels in the brain or on the oxidative stress biomarkers) system in the processing of anxiety and fear and how CB1 receptors are necessary. The results from these interdisciplinary experi- may modulate fear extinction. Pharmacol Res 56:367–381 ments may provide new information concerning the therapeu- 14. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Involvement of CB1 cannabinoid receptors in emotional tically beneficial properties of the ECS in the brain. behaviour. Psychopharmacology 159:379–387 15. Metna-Laurent M, Soria-Gomez E, Verrier D, Conforzi M, Jego P, Lafenetre P, Marsicano G (2012) Bimodal control of fear-coping Compliance with Ethical Standards strategies by CB(1) cannabinoid receptors. J Neurosci 32:7109– 7118 Conflict of Interest The authors declare that they have no conflict of 16. Steiner MA, Wotjak CT (2008) Role of the endocannabinoid sys- interest. tem in regulation of the hypothalamic-pituitary-adrenocortical ax- is. Prog Brain Res 170:397–432 Open Access This article is distributed under the terms of the Creative 17. Trezza V,Campolongo P (2013) The endocannabinoid system as a Commons Attribution 4.0 International License (http:// possible target to treat both the cognitive and emotional features of creativecommons.org/licenses/by/4.0/), which permits unrestricted use, post-traumatic stress disorder (PTSD). Front Behav Neurosci 7: distribution, and reproduction in any medium, provided you give appro- 100 priate credit to the original author(s) and the source, provide a link to the 18. Morena M, Roozendaal B, Trezza V,Ratano P,Peloso A, Hauer D, Creative Commons license, and indicate if changes were made. Atsak P, Trabace L et al (2014) Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training. Proc Natl Acad Sci U S A 111(51):18333– References 18338 19. Ruiz-Valdepeñas L, Martínez-Orgado JA, Benito C, Millán Á, Tolón RM, Romero JJ (2011) Cannabidiol reduces 1. Fernández-Ruiz J, Berrendero F, Hernández ML, Ramos JA lipopolysaccharide-induced vascular changes and inflammation (2000) The endogenous cannabinoid system and brain develop- in the mouse brain: an intravital microscopy study. J ment. Trends Neurosci 23(1):14–20 Neuroinflammation 8(1):5 2. Fride E (2008) Multiple roles for the endocannabinoid system 20. Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, during the earliest stages of life: pre- and postnatal development. Morikawa M, Inada T et al (2010) Brain cannabinoid CB2 recep- J Neuroendocrinol 1:75–81 tor in schizophrenia. Biol Psychiatry 67(10):974–982 Mol Neurobiol

21. Tong D, He S, Wang L, Jin L, Si P, Cheng X (2013) Association of the memory consolidation and retrieval mechanisms. Neurobiol single-nucleotide polymorphisms in the 2 Learn Mem 90:1–9 gene with schizophrenia in the Han Chinese population. J Mol 38. Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels Neurosci 51(2):454–460 DA, Riddick M, Dowell S et al (2007) The novel endocannabinoid 22. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, receptor GPR55 is activated by atypical cannabinoids but does not Perchuk A, Mora Z et al (2008) Brain neuronal CB2 cannabinoid mediate their vasodilator effects. Br J Pharmacol 152(5):825–831 receptors in drug abuse and depression: from mice to human sub- 39. Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory jects. PLoS One 3(2):e1640 therapeutics. Nat Rev Immunol 5:400–411 23. Minocci D, Massei J, Martino A, Milianti M, Piz L, Di Bello D, 40. Barzegar S, Komaki A, Shahidi S, Sarihi A, Mirazi N, Salehi I Sbrana A, Martinotti E et al (2011) Genetic association between (2015) Effects of cannabinoid and glutamate receptor antagonists bipolar disorder and 524A>C (Leu133Ile) polymorphism of and their interactions on learning and memory in male rats. CNR2 gene, encoding for CB2 cannabinoid receptor. J Affect Pharmacol Biochem Behav 131:87–90 Disord 134(1–3):427–430 41. Godlewski G, Offertáler L, Wagner JA, Kunos G (2009) 24. Ortega-Alvaro A, Aracil-Fernández A, García-Gutiérrez MS, Receptors for acylethanolamides—GPR55 and GPR119. Navarrete F, Manzanares J (2011) Deletion of CB2 cannabinoid Prostaglandins Other Lipid Mediat 89:105–111 receptor induces schizophrenia-related behaviors in mice. 42. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng – Neuropsychopharmacology 36(7):1489 1504 HH, George SR, O’Dowd BF (1999) Identification and cloning of 25. García-Gutiérrez MS, Ortega-Álvaro A, Busquets-García A, three novel human G protein-coupled receptor genes GPR52, Pérez-Ortiz JM, Caltana L, Ricatti MJ, Brusco A, Maldonado R PsiGPR53 and GPR55: GPR55 is extensively expressed in human et al (2013) Synaptic plasticity alterations associated with memory brain. Brain Res Mol Brain Res 64(2):193–198 impairment induced by deletion of CB2 cannabinoid receptors. 43. Henstridge CM, Balenga NA, Kargl J, Andradas C, Brown AJ, Irving – Neuropharmacology 73:388 396 A, Sanchez C, Waldhoer M (2011) Minireview: recent developments 26. Kim J, Li Y (2015) Chronic activation of CB2 cannabinoid recep- in the physiology and pathology of the lysophosphatidylinositol- tors in the hippocampus increases excitatory synaptic transmis- sensitive receptor GPR55. Mol Endocrinol 25(11):1835–1848 – sion. J Physiol 593(4):871 886 44. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, 27. Andó RD, Bíró J, Csölle C, Ledent C, Sperlágh B (2012) The Leonova J, Elebring T, Nilsson K et al (2007) The orphan receptor inhibitory action of exo- and endocannabinoids on [3H]GABA GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152: release are mediated by both CB1 and CB2 receptors in the mouse 1092–1101 – hippocampus. Neurochem Int 60(2):145 152 45. Oka S, Toshida T, Maruyama K, Nakajima K, Yamashita A, 28. García-Gutiérrez MS, García-Bueno B, Zoppi S, Leza JC, Sugiura T (2009) 2-Arachidonoyl-sn-glycero-3-phosphoinositol: Manzanares J (2012) Chronic blockade of cannabinoid CB2 re- a possible natural ligand for GPR55. J Biochem 145:13–20 ceptors induces anxiolytic-like actions associated with alterations 46. Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving in GABA-A receptors. Brit J Pharmacol 165(4):951–964 AJ (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol pro- 29. Morgan NH, Stanford IM, Woodhall GL (2009) Functional CB2 motes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB type cannabinoid receptors at CNS synapses. Neuropharmacology J 23(1):183–193 57(4):356–368 47. Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) 30. Anand P, Whiteside G, Fowler CJ, Hohmann AG (2009) Targeting Identification of GPR55 as a lysophosphatidylinositol receptor. CB2 receptors and the endocannabinoid system for the treatment Biochem Biophys Res Commun 362(4):928–934 of pain. Brain Res Rev 60(1):255–266 48. Ross RA (2009) The enigmatic pharmacology of GPR55. Trends 31. Navarrete F, Pérez-Ortiz JM, Manzanares J (2012) Cannabinoid – CB2 receptor-mediated regulation of impulsive-like behaviour in Pharmacol Sci 30(3):156 163 DBA/2 mice. Brit J Pharmacol 165(1):260–273 49. Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, 32. Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Pedraza M, Mondala H et al (2008) A role for intestinal endocrine Gottshall SL, Mark L, Pearson MS et al (2005) Pharmacological cell-expressed G protein-coupled receptor 119 in glycemic control and pharmacokinetic characterization of the cannabinoid receptor by enhancing glucagon-like peptide-1 and glucose-dependent – 2 agonist, GW405833, utilizing rodent models of acute and chron- insulinotropic peptide release. Endocrinology 149:2038 2047 ic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48(5): 50. Lauffer LM, Lakoubov R, Brubaker PL (2009) GPR119 is essen- 658–672 tial for -induced glucagon-like peptide-1 se- 33. Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, Yang HJ, Bi cretion from the intestinal enteroendocrine L-cell. Diabetes 58: – GH et al (2011) Brain cannabinoid CB2 receptors modulate co- 1058 1066 caine’s actions in mice. Nat Neurosci 14(9):1160–1166 51. Overton HA, Fyfe MC, Reynet C (2008) GPR119, a novel G 34. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, protein-coupled receptor target for the treatment of type 2 diabetes – Mackie K, Stella N, Makriyannis A et al (2005) Neuroscience: and obesity. Br J Pharmacol 153(1):76 81 identification and functional characterization of brainstem canna- 52. Ameri A (2009) The effects of cannabinoids on the brain. Prog binoid CB2 receptors. Science 310(5746):329–332 Neurbiol 58:315–348 35. den Boon FS, Chameau P, Schaafsma-Zhao Q, van Aken W, Bari 53. Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control M, Oddi S, Kruse CG, Maccarrone M et al (2012) Excitability of of pain initiation by endogenous cannabinoids. Nature (Lond) prefrontal cortical pyramidal neurons is modulated by activation 394:277–281 of intracellular type-2 cannabinoid receptors. Proc Nat Acad Sci 54. Di Marzo V,Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza USA 109(9):3534–3539 F, Miura GI et al (2001) Leptin-regulated endocannabinoids are 36. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner involved in maintaining food intake. Nature (Lond) 410:822–825 TI (1999) Increased mortality, hypoactivity, and hypoalgesia in 55. Grotenhermen F (2004) The pharmacology of cannabinoids. cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci U Neuro Endocrinol Lett 25(1/2):14–23 S A 96(10):5780–5785 56. Hughes RN (2004) The value of spontaneous alternation behavior 37. De Oliveira AL, Genro BP, Diehl F, Quillfeldt JA (2008) (SAB) as a test of retention in pharmacological investigations of Differential role of the hippocampal endocannabinoid system in memory. Neurosci Biobehav Rev 28(5):497–505 Mol Neurobiol

57. Iversen LL (2000) The science of marijuana (review book). receptors in the CA1 region of the dorsal hippocampus impairs Oxford University Press, Oxford object recognition long-term memory. Neurobiol Learn Mem 90: 58. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, 374–381 Böhme GA, Imperato A et al (1999) Unresponsiveness to canna- 77. Maćkowiak M, Chocyk A, Dudys D, Wedzony K (2009) binoids and reduced addictive effects of opiates in CB1 receptor Activation of CB1 cannabinoid receptors impairs memory con- knockout mice. Science 283(5400):401–404 solidation and hippocampal polysialylated neural cell adhesion 59. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, molecule expression in contextual fear conditioning. Cannich A, Azad SC, Cascio MG et al (2003) CB1 cannabinoid Neuroscience 158(4):1708–1716 receptors and on-demand defense against excitotoxicity. Science 78. Yim TT, Hong NS, Ejaredar M, McKenna JE, McDonald RJ (Wash DC) 302:84–88 (2008) Post-training CB1 cannabinoid receptor agonist activation 60. Riebe CJ, Wotjak CT (2011) Endocannabinoids and stress. Stress disrupts long-term consolidation of spatial memories in the hippo- 14:384–397 campus. Neuroscience 151:929–936 61. Terranova JP, Storme JJ, Lafon N, Péŕio A, Rinaldi-Carmona M, 79. Arenos JD, Musty RE, Bucci DJ (2006) Blockade of cannabinoid Le Fur G, Soubrié P (1996) Improvement of memory in rodents by CB1 receptors alters contextual learning and memory. Eur J the selective CB1 cannabinoid receptor antagonist, SR 141716. Pharmacol 539:177–183 – Psychopharmacology 126(2):165 172 80. De Oliveira A, Genro BP, Breda RV, Pedroso MF, Da Costa JC, 62. Bohme GA, Laville M, Ledent C, Parmentier M, Imperato A Quillfeldt JA (2006) AM251, a selective antagonist of the CB1 (2000) Enhanced long-term potentiation in mice lacking cannabi- receptor, inhibits the induction of long-term potentiation and in- – noid CB1 receptors. Neuroscience 95(1):5 7 duces retrograde amnesia in rats. Brain Res 1075:60–67 63. Kruk-Slomka M, Boguszewska-Czubara A, Slomka T, 81. De Oliveira AL, De Oliveira LF, Camboim C, Diehl F, Genro BP, Budzynska B, Biala G (2016a) Correlations between the Lanziotti VB, Quillfeldt JA (2005) Amnestic effect of memory-related behavior and the level of oxidative stress bio- intrahippocampal AM251, a CB1-selective blocker, in the inhibi- markers in the mice brain, provoked by an acute administration tory avoidance, but not in the open field habituation task, in rats. of CB receptor ligands. Neural Plast. doi:10.1155/2016/9815092 Neurobiol Learn Mem 83:119–124 64. Kruk-Slomka M, Biala G (2016) CB1 receptors in the formation 82. Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, of the different phases of memory-related processes in the inhibi- McGaugh JL, Cuomo V (2009) Endocannabinoids in the rat – tory avoidance test in mice. Behav Brain Res 301:84 95 basolateral amygdala enhance memory consolidation and enable 65. Puighermanal E, Busquets-Garcia A, Maldonado R, Ozaita A glucocorticoid modulation of memory. Proc Natl Acad Sci U S A (2012) Cellular and intracellular mechanisms involved in the cog- 106:4888–4893 nitive impairment of cannabinoids. Philos Trans R Soc Lond Ser 83. Ganon-Elazar E, Akirav I (2009) Cannabinoid receptor activation B Biol Sci 367(1607):3254–3263 in the basolateral amygdala blocks the effects of stress on the 66. Zarrindast MR, Navaeian M, Nasehi M (2011) Influence of three- conditioning and extinction of inhibitory avoidance. J Neurosci day -treatment upon impairment of memory consolida- 29(36):11078–11088 tion induced by cannabinoid infused into the dorsal hippocampus 84. Jamali-Raeufy N, Nasehi M, Zarrindast MR (2011) Influence of in rats. Neurosci Res 69(1):51–59 N-methyl D-aspartate receptor mechanism on WIN55,212-2-in- 67. Abush H, Akirav I (2010) Cannabinoids modulate hippocampal duced amnesia in rat dorsal hippocampus. Behav Pharmacol memory and plasticity. Hippocampus 20(10):1126–1138 22(7):645–654 68. Mazzola C, Medalie J, Scherma M, Panlilio LV, Solinas M, Tanda 85. Moshfegh A, Babaei P, Oryan S, Soltani B, Zarrindast MR (2011) G, Drago F, Cadet JL et al (2009) Fatty acid amide hydrolase Involvement of dorsal hippocampal alpha-1-adrenergic receptors (FAAH) inhibition enhances memory acquisition through activa- in the effect of WIN55,212-2 on memory retrieval in inhibitory tion of PPAR-alpha nuclear receptors. Learn Mem 16:332–337 avoidance task. Neurosci Lett 489:69–73 69. Pamplona FA, Takahashi RN (2006) WIN55,212-2 impairs con- textual fear conditioning through the activation of CB1 cannabi- 86. Basavarajappa BS, Nagre NN, Xie S, Subbanna S (2014) noid receptors. Neurosci Lett 397:88–92 Elevation of endogenous anandamide impairs LTP, learning, and 70. Schneider M, Schömig E, Leweke FM (2008) Acute and chronic memory through CB1 receptor signaling in mice. Hippocampus – cannabinoid treatment differentially affects recognition memory 24:808 818 and social behavior in pubertal and adult rats. Addict Biol 13: 87. Bucherelli C, Baldi E, Mariottini C, Passani MB, Blandina P 345–357 (2006) Aversive memory reactivation engages in the amygdala 71. Wise LE, Long KA, Abdullah RA, Long JZ, Cravatt BF, Lichtman only some neurotransmitters involved in consolidation. Learn – AH (2012) Dual fatty acid amide hydrolase and monoacylglycerol Mem 13(4):426 430 lipase blockade produces THC-like Morris water maze deficits in 88. Takahashi RN, Pamplona FA, Fernandes MS (2005) The canna- mice. ACS Chem Neurosci 3(5):369–378 binoid antagonist SR141716A facilitates memory acquisition and 72. Campolongo P, Ratano P, Manduca A, Scattoni ML, Palmery M, consolidation in the mouse elevated T-maze. Neurosci Lett 380(3): – Trezza V, Cuomo V (2012) The endocannabinoid transport inhibitor 270 275 AM404 differentially modulates recognition memory in rats depend- 89. Wolff MC, Leander JD (2003) SR141716A, a cannabinoid CB1 ing on environmental aversiveness. Front Behav Neurosci 6:11 receptor antagonist, improves memory in a delayed radial maze 73. Kim JJ, Fanselow M (1992) Modality-specific retrograde amnesia task. Eur J Pharmacol 477(3):213–217 of fear. Science 256:675–676 90. Rinaldi-Carmona M, Barth F, Heaulme M, Alonso R, Shire D, 74. Phillips RG, LeDoux JE (1992) Differential contribution of amyg- Congy C, Soubrie P, Breliere JC et al (1995) Biochemical and dala and hippocampus to cued and contextual fear conditioning. pharmacological characterization of SR141716A, the first potent Behav Neurosci 106:274–285 and selective brain cannabinoid receptor antagonist. Life Sci 75. Marchalant Y, Cerbai F, Brothers HM, Wenk GL (2008) 56(23–24):1941–1947 Cannabinoid receptor stimulation is anti-inflammatory and im- 91. Pertwee RG (2005) Inverse agonism and neutral antagonism at proves memory in old rats. Neurobiol Aging 29(12):1894–1901 cannabinoid CB1 receptors. Life Sci 76:1307–1324 76. Clarke JR, Rossato JI, Monteiro S, Bevilaqua LRM, Izquierdo I, 92. Robinson L, McKillop-Smith S, Ross NL, Pertwee RG, Hampson Cammarota M (2008) Posttraining activation of CB1 cannabinoid RE, Platt B, Riedel G (2008) Hippocampal endocannabinoids Mol Neurobiol

inhibit spatial learning and limit spatial memory in rats. 105. Atsak P, Roozendaal B, Campolongo P (2012) Role of the Psychopharmacology 198(4):551–563 endocannabinoid system in regulating glucocorticoid effects on 93. Lichtman AH (2000) SR141716A enhances spatial memory as memory for emotional experiences. Neuroscience 204:104–116 assessed in a radial-arm maze task in rats. Eur J Pharmacol 404: 106. Degroot A, Nomikos GG (2004) Genetic deletion and pharmaco- 175–179 logical blockade of CB1 receptors modulates anxiety in the shock- 94. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, probe burying test. Eur J Neurosci 20:1059–1064 Cascio MG, Hermann H, Tang J et al (2002) The endogenous 107. Jacob W, Marsch R, Marsicano G, Lutz B, Wotjak CT (2012) cannabinoid system controls extinction of aversive memories. Cannabinoid CB1 receptor deficiency increases contextual fear Nature 418:530–534 memory under highly aversive conditions and long-term potenti- – 95. Tan H, Lauzon NM, Bishop SF, Chi N, Bechard M, Laviolette SR ation in vivo. Neurobiol Learn Mem 98:47 55 (2011) Cannabinoid transmission in the basolateral amygdala 108. Maccarrone M, Valverde O, Barbaccia ML, Castane A, modulates fear memory formation via functional inputs to the Maldonado R, Ledent C, Parmentier M, Finazzi-Agrò A (2002) prelimbic cortex. J Neurosci 31(14):5300–5312 Age-related changes of anandamide metabolism in CB1 cannabi- 96. Roche M, O’Connor E, Diskin C, Finn DP (2007) The effects of noid receptor knockout mice: correlation with behaviour. Eur J – CB1 receptors antagonism in the right basolateral amygdala on Neurosci 15:1178 1186 conditioned fear and associated analgesia in rats. Eur J Neurosci 109. Reibaud M, Obinu MC, Ledent C, Parmentier M, Bohme GA, 26:2643–2653 Imperato A (1999) Enhancement of memory in cannabinoid – 97. Riedel G, Davies SN (2005) Cannabinoid function in learning, CB1 receptor knock-out mice. Eur J Pharmacol 379:R1 R2 memory and plasticity. Handb Exp Pharmacol 168:445–477 110. Fanselow MS (2000) Contextual fear, gestalt memories and the hippocampus. Behav Brain Res 110(1–2):73–81 98. Lin Q, Yang Q, Liu D, Sun Z, Dang H, Liang J, Wang YX, Chen J 111. Sacchetti B, Lorenzini CA, Baldi E, Tassoni G, Bucherelli C et al (2011) Hippocampal endocannabinoids play an important (1999) Auditory thalamus, dorsal hippocampus, basolateral amyg- role in induction of long-term potentiation and regulation of con- dala and perirhinal cortex role in the consolidation of conditioned textual fear memory formation. Brain Res Bull 86:139–145 freezing to context and to acoustic conditioned stimulus in the rat. 99. Wise LE, Iredale PA, Lichtman AH (2008) The cannabinoid CB1 J Neurosci 19(21):9570–9578 receptor antagonist CE prolongs spatial memory duration in a rat 112. Li Y, Kim J (2016) CB2 cannabinoid receptor knockout in mice delayed radial arm maze memory task. Eur J Pharmacol 590(1–3): – impairs contextual long-term memory and enhances spatial work- 246 249 ing memory. Neural Plast doi. doi:10.1155/2016/9817089 100. Bolognini D, Cascio MG, Parolaro D, Pertwee RG (2012) AM630 113. Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH (2007) behaves as a protean ligand at the human cannabinoid CB2 recep- Inhibition of fatty-acid amide hydrolase accelerates acquisition and – tor. Brit J Pharmacol 165(8):2561 2574 extinction rates in a spatial memory task. Neuropsychopharmacology 101. Häring M, Marsicano G, Lutz B, Monory K (2007) Identification 32:1032–1041 of the cannabinoid receptor type 1 in serotonergic cells of raphe 114. Hasanein P, Teimuri Far M (2015) Effects of URB597 as an in- – nuclei in mice. Neuroscience 146(3):1212 1219 hibitor of fatty acid amide hydrolase on WIN55, 212-2-induced 102. Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, learning and memory deficits in rats. Pharmacol Biochem Behav Makriyannis A, Pertwee RG (1999) Agonist-inverse agonist char- 131:130–135 acterization at CB1 and CB2 cannabinoid receptors of L759633, 115. Varvel SA, Cravatt BF, Engram AE, Lichtman AH (2005) Fatty L759656 and AM630. Brit J Pharmacol 126(3):665–672 acid amide hydrolase (−/−) mice exhibit an increased sensitivity to 103. Hill MN, McEwen BS (2010a) Involvement of the endocannabinoid the disruptive effects of anandamide or oleamide in a working system in the neurobehavioural effects of stress and glucocorticoids. memory water maze task. J Pharmacol Exp Ther 31:251–257 Prog Neuro-Psychopharmacol Biol Psychiatry 34:791–797 116. Panlilio LV, Justinova Z, Goldberg SR (2013) Inhibition of FAAH 104. Marsicano G, Lafenêtre P (2009) Roles of the endocannabinoid sys- and activation of PPAR: new approaches to the treatment of cogni- tem in learning and memory. Curr Top Behav Neurosci 1:201–230 tive dysfunction and drug addiction. Pharmacol Ther 138:84–102